We report here the first example of a sulfo-click conjugation reaction to be applied to modified nucleosides. The reaction, which proceeds rapidly (k similar to 2.0 x 10(-1) M-1 s(-1) at 25 degrees C) under aqueous biocompatible conditions in the ribo- and deoxyribonucleoside series, affords the corresponding conjugated products in excellent yields. Furthermore, we demonstrate the orthogonality of the reaction with the copper-catalyzed azide-alkyne click reaction (CuAAC) by performing a one-pot dual labeling of a nucleoside carrying two orthogonal azido groups.